Triazolopyrazine

ABSTRACT

Disclosed are compounds of the formula (I) 
     
       
         
         
             
             
         
       
     
     wherein the groups R 1  to R 3  have the meanings given in the claims and in the specification. The compounds of the invention are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation pharmaceutical preparations containing such compounds and their uses as a medicament.

This invention relates to compounds of the general formula (I)

wherein the groups R¹ to R³ have the meanings given in the claims and inthe specification. The compounds of the invention are suitable for thetreatment of diseases characterized by excessive or abnormal cellproliferation, pharmaceutical preparations containing such compounds andtheir uses as a medicament. The compounds of the invention are BRD4inhibitors.

BACKGROUND OF THE INVENTION

Histone acetylation is most usually associated with the activation ofgene transcription, as the modification loosens the interaction of theDNA and the histone octomer by changing the electrostatics. In additionto this physical change, specific proteins bind to acetylated lysineresidues within histones to read the epigenetic code. Bromodomains aresmall (about 110 amino acid) distinct domains within proteins that bindto acetylated lysine resides commonly but not exclusively in the contextof histones. There is a family of around 50 proteins known to containbromodomains, and they have a range of functions within the cell.

The BET family of bromodomain containing proteins comprises 4 proteins(BRD2, BRD3, BRD4 and BRD-T) which contain tandem bromodomains capableof binding to two acetylated lysine residues in close proximity,increasing the specificity of the interaction. Recent research hasestablished a compelling rationale for targeting BRD4 in cancer. BRD4remains bound to transcriptional start sites of genes expressed duringthe entry into the G1 phase of the cell cycle, and is functioning torecruit the positive transcription elongation factor complex (P-TEFb),resulting in increased expression of growth promoting genes (Yang andZhou, Mol. Cell. Biol. 28, 967, 2008). Importantly, BRD4 has beenidentified as a component of a recurrent t(15;19) chromosomaltranslocation in an aggressive form of human squamous carcinoma (Frenchet al., Cancer Res. 63, 304, 2003). Such translocations express thetandem N-terminal bromodomains of BRD4 as an in-frame chimera with theNUT (nuclear protein in testis) protein, genetically defining theso-called NUT midline carcinoma (NMC). Functional studies inpatient-derived NMC cell lines have validated the essential role of theBRD4-NUT oncoprotein in maintaining the proliferation and thedifferentiation block of these malignant cells. In addition, BRD4 hasbeen identified as a critical sensitivity determinant in a geneticallydefined AML mouse model (Zuber et al., Nature 2011 478(7370):524-8).Suppression of BRD4 led to robust anti-leukemic effects in vitro and invivo, accompanied by terminal myeloid differentiation. Interestingly,BRD4 inhibition triggered MYC down-regulation in a broad array of mouseand human leukemia cell lines examined, indicating that small moleculeBRD4 inhibitors may provide a means to suppress the MYC pathway in arange of AML subtypes.

Finally, the other family members of the BET family have also beenreported to have some function in controlling or executing aspects ofthe cell cycle, and have been shown to remain in complex withchromosomes during cell division—suggesting a role in the maintenance ofepigenetic memory (Leroy et ai, Mol. Cell. 2008 30(1):51-60).

Examples of bromodomain inhibitors are benzodiazepine derivatives,disclosed in WO2011/054553, and imidazo [4,5] quinoline derivatives,disclosed in WO2011/054846.

Thus, there is the need to provide BRD4 inhibitors useful for theprevention and/or treatment of diseases characterized by excessive orabnormal cell proliferation, such as cancer.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of formula (I)

-   -   wherein,    -   R¹ is —C₁₋₃alkyl or —C₁₋₃haloalkyl; R² is selected from —NHR⁴,        —C₁₋₅alkyl, —C₁₋₅haloalkyl, halogen and —S—C₁₋₃alkyl;    -   R³ is a 5-12 membered heteroaryl, which group is substituted        with —X—R¹⁰ and optionally further substituted with one ore more        groups independently selected from R⁹;    -   R⁴ is selected from —C₁₋₅alkyl and 5-12 membered        heterocycloalkyl, which heterocycloalkyl can be optionally        substituted with one or more groups independently selected from        R⁵;    -   R⁵ is selected from —C₁₋₅alkyl, —C₁₋₅haloalkyl and        —C₁₋₃alkylene-O—C₁₋₃alkyl;    -   R⁹ is selected from —C₁₋₅alkyl, —O—C₁₋₅alkyl, —N(C₁₋₅alkyl)₂,        halogen, —C₁₋₃alkylene-O—C₁₋₃alkyl, —C₁₋₅alkylene-N(—C₁₋₅alkyl,        —C₁₋₅alkyl), 5-12 membered heterocycloalkyl, wherein the        heterocycloalkyl group can be optionally substituted with one or        more groups independently selected from ═O, —C₁₋₃alkyl, or    -   R⁹ is selected from —C₆₋₁₀aryl and 5-12 membered heteroaryl,        wherein the aryl and heteroaryl groups can be optionally and        independently substituted with one ore more groups selected from        halogen, —C₁₋₃alkyl, —O—C₁₋₃alkyl, —C₁₋₃haloalkyl,        —O—C₁₋₃haloalkyl, —N(C₁₋₅alkyl, C₁₋₅alkyl) and —NH—C₁₋₅alkyl;    -   X is —C₁₋₃alkylene- or —O—;    -   R¹⁰ is-C₆₋₁₀aryl or 5-12 membered heteroaryl, each of which        groups can be optionally substituted with one or more groups        selected from halogen, —C₁₋₃alkyl, —O—C₁₋₃alkyl, —C₁₋₃haloalkyl,        —O—C₁₋₃haloalkyl;    -   wherein the compounds of formula (I) may be optionally be        present in the form of salts.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein R¹ is —CH₃.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein R² is —NHR⁴ and R⁴ is a 5-6 membered heterocycloalkyl,optionally substituted as defined herein in the description and claims.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein R² is —NHR⁴ and R⁴ is tetrahydrofuran or piperidine,wherein the piperidine is substituted with one group selected from —CH₃,—CH₂CH₃, —CH₂CH₂CH₃ and —(CH₂)₂—O—CH₃.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein R² is —NHR⁴ and R⁴ is —C₁₋₃alkyl.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein R² is —NHR⁴ and R⁴ is —CH₃ or —CH(CH₃)₂.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein R² is —C₁₋₃alkyl.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein R³ is a 5-9 membered heteroaryl substituted with —X—R¹⁰ andoptionally further substituted with one or more groups independentlyselected from R⁹, wherein R⁹, R¹⁰ and X are as defined herein in thedescription and the claims.

Preferably, R³ is optionally further substituted with one or two R⁹.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein —X—R¹⁰ is selected from —CH₂-phenyl, —CH(CH₃)-phenyl,—CH₂-pyridyl, —CH(CH₃)-pyridyl, —O-phenyl, each of which phenyl orpyridyl groups is optionally substituted with —F or —CH₃.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein —X—R¹⁰ is selected from —CH₂-phenyl, —CH₂-pyridyl,—CH(CH₃)-phenyl, —CH(CH₃)-pyridyl, each of which pyridyl or phenyl groupis optionally substituted with —F or —CH₃.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein R³ is selected from pyrazolyl imidazol, benzimidazolyl,imidazopyridine and imidazopyrimidine and R³ is substituted with —X—R¹⁰and R³ is optionally further substituted with one or more groupsindependently selected from R⁹, wherein R⁹, R¹⁰ and X are as definedherein in the description and the claims.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein R⁹ is independently selected from —C₁₋₃alkyl, —O—C₁₋₃alkyl,—N(C₁₋₃alkyl)₂, phenyl and 6 membered heterocycloalkyl, whichheterocycloalklyl can be optionally substituted with one or more groupsindependently selected ═O and —C₁₋₃alkyl.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein R³ is imidazopyridine or benzimidazol substituted with—CH₂-phenyl or —CH₂-pyridyl, —CH(CH₃)-pyridyl and optionally furthersubstituted with —C₁₋₃alkyl or 5-12 membered heterocycloalkyl whereinthe heterocycloalkyl group can be optionally substituted with one ormore groups independently selected from —C₁₋₃alkyl.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein R³ is imidazopyridine or benzimidazol substituted with—CH₂-phenyl, —CH(CH₃)-pyridyl or —CH₂-pyridyl and substituted with—CH(CH₃)₂ or morpholinyl or piperazinyl, wherein the morpholinyl orpiperazinyl groups is optionally substituted with one or more groupsselected from —C₁₋₃alkyl.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein the 5-9 membered heteroaryl in R³ position is attached tothe core of the structure via a carbon atom.

In a preferred embodiment, the invention relates to compounds of formula(I), wherein the pyridyl moiety in R¹⁰ position is bound to —X— in2-position.

In a further embodiment, the invention relates to compounds of formula(I) for use in the treatment of cancer.

In a further embodiment, the invention relates to compound of generalformula (I) according to anyone of the embodiments described herein inthe description and the claims—or the pharmaceutically acceptable saltsthereof—for use in the treatment and/or prevention of cancer.

In a further embodiment, the invention relates to pharmaceuticalpreparation comprising as active substance one or more compounds ofgeneral formula (I) according to anyone of the embodiments describedherein in the description and the claims optionally in combination withconventional excipients and/or carriers.

In a further embodiment, the invention relates to pharmaceuticalpreparation comprising a compound of general formula (I) according toanyone of the embodiments described herein in the description and theclaims—or one of the pharmaceutically acceptable salts thereof—and atleast one other cytostatic or cytotoxic active substance, different fromformula (I).

The present invention further relates to hydrates, solvates, polymorphs,metabolites, derivatives and prodrugs of compounds of general formula(I).

The present invention further relates to a pharmaceutically acceptablesalt of a compound of general formula (I) with anorganic or organicacids or bases.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—as medicaments.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—for use in a methodfor treatment of the human or animal body.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—for use in thetreatment and/or prevention of cancer, infections, inflammations andautoimmune diseases.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—for use in a methodfor treatment and/or prevention of cancer, infections, inflammations andautoimmune diseases in the human and animal body.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—for use in thetreatment and/or prevention of cancer.

In another aspect the invention relates to the use of the compounds ofgeneral formula (I)—or the pharmaceutically acceptable salts thereof—inthe treatment and/or prevention of cancer.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—for use in a methodfor treatment and/or prevention of cancer in the human or animal body.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—for use in thetreatment and/or prevention of hematopoietic malignancies, preferablyAML, MM.

In another aspect the invention relates to compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—for use in thetreatment and/or prevention of solid tumors, preferably to lung, liver,colon, brain, thyroid, pancreas, breast, ovary and prostate cancer.

In another aspect the invention relates to a process for the treatmentand/or prevention of cancer comprising administering a therapeuticallyeffective amount of a compound of general formula (I)—or one of thepharmaceutically acceptable salts thereof—to a human being.

In another aspect the invention relates to a pharmaceutical preparationcontaining as active substance one or more compounds of general formula(I)—or the pharmaceutically acceptable salts thereof—optionally incombination with conventional excipients and/or carriers.

In another aspect the invention relates to a pharmaceutical preparationcomprising a compound of general formula (I)—or one of thepharmaceutically acceptable salts thereof—and at least one othercytostatic or cytotoxic active substance, different from formula (I).

Definitions

Terms that are not specifically defined here have the meanings that areapparent to the skilled man in the light of the overall disclosure andthe context as a whole.

As used herein, the following definitions apply, unless statedotherwise.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, —C₁₋₅alkylmeans an alkyl group or radical having 1 to 5 carbon atoms. In general,for groups comprising two or more subgroups, the first named sub-groupis the radical attachment point, for example the substitutent—C₁₋₅alkyl-C₃₋₁₀cylcoalkyl, means a C₃₋₁₀cylcoalkyl group which is boundto a C₁₋₅alkyl, the latter of which is bound to the core structure or tothe group to which the substitutent is attached.

The indication of the number of members in groups that contain one ormore heteroatom(s) (heteroalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocycylalkyl) relates to the total atomic number ofall the ring members or chain members or the total of all the ring andchain members.

The person skilled in the art will appreciate that substituent groupscontaining a nitrogen atom can also be indicated as amine or amino.Similarly, groups containing oxygen atom can also be indicated with-oxy, like for example alkoxy. Groups containing —C(O)— can also beindicated as carboxy; groups containing —NC(O)— can also be indicated asamide; groups containing —NC(O)N— can also be indicated as urea; groupscontaining —NS(O)₂— can also be indicated as sulfonamide.

Alkyl denotes monovalent, saturated hydrocarbon chains, which may bepresent in both linear and branched form. If an alkyl is substituted,the substitution may take place independently of one another, by mono-or polysubstitution in each case, on all the hydrogen-carrying carbonatoms.

The term “C₁₋₅-alkyl” includes for example methyl (Me; —CH₃), ethyl (Et;—CH₂CH₃), 1-propyl (n-propyl; n-Pr; —CH₂CH₂CH₃), 2-propyl (i-Pr;iso-propyl; —CH(CH₃)₂), 1-butyl (n-butyl; n-Bu; —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (iso-butyl; i-Bu; —CH₂CH(CH₃)₂), 2-butyl (sec-butyl;sec-Bu; —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (tert-butyl; t-Bu; —C(CH₃)₃),1-pentyl (n-pentyl; —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃),3-pentyl (—CH(CH₂CH₃)₂), 3-methyl-1-butyl (iso-pentyl; —CH₂CH₂CH(CH₃)₂),2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂),2,2-dimethyl-1-propyl (neo-pentyl; —CH₂C(CH₃)₃), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃).

By the terms propyl, butyl, pentyl, etc. without any further definitionare meant saturated hydrocarbon groups with the corresponding number ofcarbon atoms, wherein all isomeric forms are included.

The above definition for alkyl also applies if alkyl is a part ofanother group such as for example C_(x-y)-alkylamino or C_(x-y)-alkyloxyor C_(x-y)-alkoxy, wherein C_(x-y)-alkyloxy and C_(x-y)-alkoxy indicatethe same group.

The term alkylene can also be derived from alkyl. Alkylene is bivalent,unlike alkyl, and requires two binding partners. Formally, the secondvalency is produced by removing a hydrogen atom in an alkyl.Corresponding groups are for example —CH₃ and —CH₂, —CH₂CH₃ and —CH₂CH₂or >CHCH₃ etc.

The term “C₁₋₄-alkylene” includes for example —(CH₂)—, —(CH₂—CH₂)—,—(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

Other examples of alkylene are methylene, ethylene, propylene,1-methylethylene, butylene, 1-methylpropylene, 1.1-dimethylethylene,1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene,2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene,etc.

By the generic terms propylene, butylene, pentylene, hexylene etc.without any further definition are meant all the conceivable isomericforms with the corresponding number of carbon atoms, i.e. propyleneincludes 1-methylethylene and butylene includes 1-methylpropylene,2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

The above definition for alkylene also applies if alkylene is part ofanother group such as for example in HO—C_(x-y)-alkyleneamino orH₂N—C_(x-y)-alkylenoxy.

Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein atleast two adjacent carbon atoms are joined together by a C═C doublebond. If in an alkyl as hereinbefore defined having at least two carbonatoms, two hydrogen atoms on adjacent carbon atoms are formally removedand the free valencies are saturated to form a second bond, thecorresponding alkenyl is formed.

Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, allyl(prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl,2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl,1-methyl-prop-1-enyl, 1-methylidenepropyl, pent-1-enyl, pent-2-enyl,pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl,3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl,hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl,2-methylidene-3-methylbutyl, 2,3-dimethyl-but-1-enyl, hexa-1,3-dienyl,hexa-1,4-dienyl, penta-1,4-dienyl, penta-1,3-dienyl, buta-1,3-dienyl,2,3-dimethylbuta-1,3-diene etc.

By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl,pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyletc. without any further definition are meant all the conceivableisomeric forms with the corresponding number of carbon atoms, i.e.propenyl includes prop-1-enyl and prop-2-enyl, butenyl includesbut-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl,1-methyl-prop-2-enyl etc.

Alkenyl may optionally be present in the cis or trans or E or Zorientation with regard to the double bond(s).

The above definition for alkenyl also applies when alkenyl is part ofanother group such as for example in C_(x-y)-alkenylamino orC_(x-y)-alkenyloxy.

Unlike alkylene, alkenylene consists of at least two carbon atoms,wherein at least two adjacent carbon atoms are joined together by a C═Cdouble bond. If in an alkylene as hereinbefore defined having at leasttwo carbon atoms, two hydrogen atoms at adjacent carbon atoms areformally removed and the free valencies are saturated to form a secondbond, the corresponding alkenylene is formed. Examples of alkenylene areethenylene, propenylene, 1-methylethenylene, butenylene,1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene,pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene,1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene etc.

By the generic terms propenylene, butenylene, pentenylene, hexenyleneetc. without any further definition are meant all the conceivableisomeric forms with the corresponding number of carbon atoms, i.e.propenylene includes 1-methylethenylene and butenylene includes1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and1,2-dimethylethenylene.

Alkenylene may optionally be present in the cis or trans or E or Zorientation with regard to the double bond(s).

The above definition for alkenylene also applies when alkenylene is apart of another group as in for example HO—C_(x-y)-alkenylenamino orH₂N—C_(x-y)-alkenylenoxy.

Unlike alkyl, alkynyl consists of at least two carbon atoms, wherein atleast two adjacent carbon atoms are joined together by a C—C triplebond. If in an alkyl as hereinbefore defined having at least two carbonatoms, two hydrogen atoms in each case at adjacent carbon atoms areformally removed and the free valencies are saturated to form twofurther bonds, the corresponding alkynyl is formed.

Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl,but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl,pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl.

By the generic terms propynyl, butynyl, pentynyl, etc. without anyfurther definition are meant all the conceivable isomeric forms with thecorresponding number of carbon atoms, i.e. propynyl includes prop-1-ynyland prop-2-ynyl, butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl,1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl.

If a hydrocarbon chain carries both at least one double bond and also atleast one triple bond, by definition it belongs to the alkynyl subgroup.

The above definition for alkynyl also applies if alkynyl is part ofanother group, as in C_(x-y)-alkynylamino or C_(x-y)-alkynyloxy, forexample.

Unlike alkylene, alkynylene consists of at least two carbon atoms,wherein at least two adjacent carbon atoms are joined together by a C—Ctriple bond. If in an alkylene as hereinbefore defined having at leasttwo carbon atoms, two hydrogen atoms in each case at adjacent carbonatoms are formally removed and the free valencies are saturated to formtwo further bonds, the corresponding alkynylene is formed.

Examples of alkynylene are ethynylene, propynylene, 1-methylethynylene,butynylene, 1-methylpropynylene, 1,1-dimethylethynylene,1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene,2,2-dimethylpropynylene, 1,2-dimethylpropynylene,1,3-dimethylpropynylene, hexynylene etc.

By the generic terms propynylene, butynylene, pentynylene, etc. withoutany further definition are meant all the conceivable isomeric forms withthe corresponding number of carbon atoms, i.e. propynylene includes1-methylethynylene and butynylene includes 1-methylpropynylene,2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.

The above definition for alkynylene also applies if alkynylene is partof another group, as in HO—C_(x-y)-alkynyleneamino orH₂N—C_(x-y)-alkynyleneoxy, for example. By heteroatoms are meant oxygen,nitrogen and sulphur atoms.

Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previouslydefined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atomsof the hydrocarbon chain independently of one another by halogen atoms,which may be identical or different. If a haloalkyl (haloalkenyl,haloalkynyl) is to be further substituted, the substitutions may takeplace independently of one another, in the form of mono- orpolysubstitutions in each case, on all the hydrogen-carrying carbonatoms.

Examples of haloalkyl (haloalkenyl, haloalkynyl) are —CF₃, —CHF₂, —CH₂F,—CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃, —CF₂CF₂CF₃, —CF₂CH₂CH₃,—CF═CF₂, —CCl═CH₂, —CBr═CH₂, —CI═CH₂, —C≡C≡CF₃, —CHFCH₂CH₃, —CHFCH₂CF₃etc.

From the previously defined haloalkyl (haloalkenyl, haloalkynyl) arealso derived the terms haloalkylene (haloalkenylene, haloalkynylene).Haloalkylene (haloalkenyl, haloalkynyl), unlike haloalkyl, is bivalentand requires two binding partners. Formally, the second valency isformed by removing a hydrogen atom from a haloalkyl.

Corresponding groups are for example —CH₂F and —CHF—, —CHFCH₂F and—CHFCHF— or >CFCH₂F etc.

The above definitions also apply if the corresponding halogen groups arepart of another group.

Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.

Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings,bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems aresaturated. In bicyclic hydrocarbon rings two rings are joined togetherso that they have at least two carbon atoms together. Inspiro-hydrocarbon rings a carbon atom (spiroatom) belongs to two ringstogether. If a cycloalkyl is to be substituted, the substitutions maytake place independently of one another, in the form of mono- orpolysubstitutions in each case, on all the hydrogen-carrying carbonatoms. Cycloalkyl itself may be linked as a substituent to the moleculevia every suitable position of the ring system.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl(octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthalene),bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl),bicyclo-[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl etc.The above definition for cycloalkyl also applies if cycloalkyl is partof another group as in C_(x-y)-cycloalkylamino or C_(x-y)-cycloalkyloxy,for example.

If the free valency of a cycloalkyl is saturated, then an alicyclicgroup is obtained. The term cycloalkylene can thus be derived from thepreviously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, isbivalent and requires two binding partners. Formally, the second valencyis obtained by removing a hydrogen atom from a cycloalkyl. Correspondinggroups are for example cyclohexyl and

(cyclohexylene).

The above definition for cycloalkylene also applies if cycloalkylene ispart of another group as in HO—C_(x-y)-cycloalkyleneamino orH₂N—C_(x-y)-cycloalkyleneoxy, for example.

Cycloalkenyl is also made up of the subgroups monocyclic hydrocarbonrings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. However,the systems are unsaturated, i.e. there is at least one C═C double bondbut no aromatic system. If in a cycloalkyl as hereinbefore defined twohydrogen atoms at adjacent cyclic carbon atoms are formally removed andthe free valencies are saturated to form a second bond, thecorresponding cycloalkenyl is obtained. If a cycloalkenyl is to besubstituted, the substitutions may take place independently of oneanother, in the form of mono- or polysubstitutions in each case, on allthe hydrogen-carrying carbon atoms. Cycloalkenyl itself may be linked asa substituent to the molecule via every suitable position of the ringsystem.

Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl,cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl,cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl,cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl,cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-dienyl,cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl,cyclohexa-2,4-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl,bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl),bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4.5]dec-2-ene etc.

The above definition for cycloalkenyl also applies when cycloalkenyl ispart of another group as in C_(x-y)-cycloalkenylamino orC_(x-y)-cycloalkenyloxy, for example. If the free valency of acycloalkenyl is saturated, then an unsaturated alicyclic group isobtained.

The term cycloalkenylene can thus be derived from the previously definedcycloalkenyl. Cycloalkenylene, unlike cycloalkenyl, is bivalent andrequires two binding partners. Formally the second valency is obtainedby removing a hydrogen atom from a cycloalkenyl. Corresponding groupsare for example cyclopentenyl and

(cyclopentenylene) etc.

The above definition for cycloalkenylene also applies whencycloalkenylene is part of another group as inHO—C_(x-y)-cycloalkenyleneamino or H₂N—C_(x-y)-cycloalkenyleneoxy, forexample.

Aryl denotes a mono-, bi- or tricyclic group with at least one aromaticcarbocycle. Preferably it denotes a monocyclic group with six carbonatoms (phenyl) or a bicyclic group with nine or ten carbon atoms (twosix-membered rings or one six-membered ring with a five-membered ring),wherein the second ring may also be aromatic or, however, may also besaturated or partially saturated. If an aryl is to be substituted, thesubstitutions may take place independently of one another, in the formof mono- or polysubstitutions in each case, on all the hydrogen-carryingcarbon atoms. Aryl itself may be linked as a substituent to the moleculevia every suitable position of the ring system.

Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl),indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl(1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl(1,2-dihydronaphthyl), fluorenyl etc.

The above definition of aryl also applies when aryl is part of anothergroup as in arylamino or aryloxy, for example.

If the free valency of an aryl is saturated, then an aromatic group isobtained.

The term arylene can also be derived from the previously defined aryl.Arylene, unlike aryl, is bivalent and requires two binding partners.Formally, the second valency is formed by removing a hydrogen atom froman aryl. Corresponding groups are e.g.

-   -   phenyl and

(o, m, p-phenylene), naphthyl and

etc.

The above definition for arylene also applies when arylene is part ofanother group as in HO-aryleneamino or H₂N-aryleneoxy for example.

Heterocyclyl denotes ring systems, which are derived from the previouslydefined cycloalkyl, cycloalkenyl and aryl by replacing one or more ofthe groups —CH₂— independently of one another in the hydrocarbon ringsby the groups —O—, —S— or —NH— or by replacing one or more of the groups═CH— by the group ═N—, wherein a total of not more than five heteroatomsmay be present, at least one carbon atom may be present between twooxygen atoms and between two sulphur atoms or between one oxygen and onesulphur atom and the ring as a whole must have chemical stability.Heteroatoms may optionally be present in all the possible oxidationstages (sulphur→sulphoxide —SO, sulphone —SO₂—; nitrogen→N-oxide).

A direct result of the derivation from cycloalkyl, cycloalkenyl and arylis that heterocyclyl is made up of the subgroups monocyclic heterorings,bicyclic heterorings, tricyclic heterorings and spiro-heterorings, whichmay be present in saturated or unsaturated form. Saturated andunsaturated, non aromatic, heterocyclyl are also defined asheterocycloalkyl. By unsaturated is meant that there is at least onedouble bond in the ring system in question, but no heteroaromatic systemis formed. In bicyclic heterorings two rings are linked together so thatthey have at least two (hetero)atoms in common. In spiro-heterorings acarbon atom (spiroatom) belongs to two rings together. If a heterocyclylis substituted, the substitutions may take place independently of oneanother, in the form of mono- or polysubstitutions in each case, on allthe hydrogen-carrying carbon and/or nitrogen atoms. Heterocyclyl itselfmay be linked as a substituent to the molecule via every suitableposition of the ring system. When the heterocyclyl has a nitrogen atom,the preferred position to bind the heterocyclyl substituent to themolecule is the nitrogen atom.

Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl,1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl,homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl,thiomorpholinyl-S-oxide, thiomorpholinyl-S, S-dioxide, 1,3-dioxolanyl,tetrahydropyranyl, tetrahydrothiopyranyl, [1.4]-oxazepanyl,tetrahydrothienyl, homothiomorpholinyl-S, S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl,dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl-S-oxide, tetrahydrothienyl-S, S-dioxide,homothiomorpholinyl-S-oxide, 2,3-dihydroazet, 2H-pyrrolyl, 4H-pyranyl,1,4-dihydropyridinyl, 8-azabicyclo[3.2.1]octyl,8-azabicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]-heptyl,8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl,2,5-diaza-bicyclo-[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl,3,8-diaza-bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl,2,6-diaza-bicyclo[3.2.2]nonyl, 1,4-dioxa-spiro[4.5]-decyl,1-oxa-3.8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl,2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl,3,9-diaza-spiro[5.5]undecyl, 2.8-diaza-spiro[4.5]decyl etc.

Further examples are the structures illustrated below, which may beattached via each hydrogen-carrying atom (exchanged for hydrogen):

The above definition of heterocyclyl also applies if heterocyclyl ispart of another group as in heterocyclylamino or heterocyclyloxy forexample.

If the free valency of a heterocyclyl is saturated, then a heterocyclicgroup is obtained.

The term heterocyclylene is also derived from the previously definedheterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent andrequires two binding partners. Formally, the second valency is obtainedby removing a hydrogen atom from a heterocyclyl. Corresponding groupsare for example piperidinyl and

2,3-dihydro-1H-pyrrolyl and

etc.

The above definition of heterocyclylene also applies if heterocyclyleneis part of another group as in HO-heterocyclyleneamino orH₂N-heterocyclyleneoxy for example.

Heteroaryl denotes monocyclic heteroaromatic rings or polycyclic ringswith at least one heteroaromatic ring, which compared with thecorresponding aryl or cycloalkyl (cycloalkenyl) contain, instead of oneor more carbon atoms, one or more identical or different heteroatoms,selected independently of one another from among nitrogen, sulphur andoxygen, wherein the resulting group must be chemically stable. Theprerequisite for the presence of heteroaryl is a heteroatom and aheteroaromatic system. If a heteroaryl is to be substituted, thesubstitutions may take place independently of one another, in the formof mono- or polysubstitutions in each case, on all the hydrogen-carryingcarbon and/or nitrogen atoms. Heteroaryl itself may be linked as asubstituent to the molecule via every suitable position of the ringsystem, both carbon and nitrogen.

Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N-oxide,pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide,imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide,thiazolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide,triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl,benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl,quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl,indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl,benzoxazolyl, pyridopyridyl, purinyl, pteridinyl, benzothiazolyl,imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide, indolyl-N-oxide,isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide,phthalazinyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide,benzothiazolyl-N-oxide, benzimidazolyl-N-oxide etc.

Further examples are the structures illustrated below, which may beattached via each hydrogen-carrying atom (exchanged for hydrogen):

The above definition of heteroaryl also applies when heteroaryl is partof another group as in heteroarylamino or heteroaryloxy, for example.

If the free valency of a heteroaryl is saturated, a heteroaromatic groupis obtained.

The term heteroarylene can therefore be derived from the previouslydefined heteroaryl. Heteroarylene, unlike heteroaryl, is bivalent andrequires two binding partners. Formally, the second valency is obtainedby removing a hydrogen atom from a heteroaryl. Corresponding groups arefor example pyrrolyl and

etc.

The above definition of heteroarylene also applies when heteroarylene ispart of another group as in HO-heteroaryleneamino orH₂N-heteroaryleneoxy, for example.

The bivalent groups mentioned above (alkylene, alkenylene, alkynyleneetc.) may also be part of composite groups (e.g. H₂N—C₁₋₄alkylene- orHO—C₁₋₄alkylene-). In this case one of the valencies is saturated by theattached group (here: —NH₂, —OH), so that a composite group of this kindwritten in this way is only a monovalent substituent over all.

By substituted is meant that a hydrogen atom which is bound directly tothe atom under consideration, is replaced by another atom or anothergroup of atoms (substituent). Depending on the starting conditions(number of hydrogen atoms) mono- or polysubstitution may take place onone atom. Substitution with a particular substituent is only possible ifthe permitted valencies of the substituent and of the atom that is to besubstituted correspond to one another and the substitution leads to astable compound (i.e. to a compound which is not convertedspontaneously, e.g. by rearrangement, cyclisation or elimination).

Bivalent substituents such as ═S, ═NR, ═NOR, ═NNRR, ═NN(R)C(O)NRR, ═N₂or the like, may only be substituted at carbon atoms, wherein thebivalent substituent ═O may also be a substituent at sulphur. Generally,substitution may be carried out by a bivalent substituent only at ringsystems and requires replacement by two geminal hydrogen atoms, i.e.hydrogen atoms that are bound to the same carbon atom that is saturatedprior to the substitution. Substitution by a bivalent substituent istherefore only possible at the group —CH₂— or sulphur atoms of a ringsystem.

Stereochemistry/Solvates/Hydrates: Unless stated otherwise a structuralformula given in the description or in the claims or a chemical namerefers to the corresponding compound itself, but also encompasses thetautomers, stereoisomers, optical and geometric isomers (e.g.enantiomers, diastereomers, E/Z isomers, etc.), racemates, mixtures ofseparate enantiomers in any desired combinations, mixtures ofdiastereomers, mixtures of the forms mentioned hereinbefore (if suchforms exist) as well as salts, particularly pharmaceutically acceptablesalts thereof. The compounds and salts according to the invention may bepresent in solvated form (e.g. with pharmaceutically acceptable solventssuch as e.g. water, ethanol etc.) or in unsolvated form. Generally, forthe purposes of the present invention the solvated forms, e.g. hydrates,are to be regarded as of equal value to the unsolvated forms.

Salts: The term “pharmaceutically acceptable” is used herein to denotecompounds, materials, compositions and/or formulations which aresuitable, according to generally recognised medical opinion, for use inconjunction with human and/or animal tissue and do not have or give riseto any excessive toxicity, irritation or immune response or lead toother problems or complications, i.e. correspond overall to anacceptable risk/benefit ratio.

The term “pharmaceutically acceptable salts” relates to derivatives ofthe chemical compounds disclosed in which the parent compound ismodified by the addition of acid or base. Examples of pharmaceuticallyacceptable salts include (without being restricted thereto) salts ofmineral or organic acids in relation to basic functional groups such asfor example amines, alkali metal or organic salts of acid functionalgroups such as for example carboxylic acids, etc. These salts include inparticular acetate, ascorbate, benzenesulphonate, benzoate, besylate,bicarbonate, bitartrate, bromide/hydrobromide, Ca-edetate/edetate,camsylate, carbonate, chloride/hydrochloride, citrate, edisylate, ethanedisulphonate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycolate, glycollylarsnilate, hexylresorcinate, hydrabamine,hydroxymaleate, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, malate, maleate, mandelate, methanesulphonate, mesylate,methylbromide, methylnitrate, methylsulphate, mucate, napsylate,nitrate, oxalate, pamoate, pantothenate, phenyl acetate,phosphate/diphosphate, polygalacturonate, propionate, salicylate,stearate, subacetate, succinate, sulphamide, sulphate, tannate,tartrate, teoclate, toluenesulphonate, triethiodide, ammonium,benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine,meglumin and procaine. Other pharmaceutically acceptable salts may beformed with cations of metals such as aluminium, calcium, lithium,magnesium, potassium, sodium, zinc, etc. (cf. also Pharmaceutical salts,Birge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention may beprepared starting from the parent compound which carries a basic oracidic functionality, by conventional chemical methods. Generally, suchsalts may be synthesised by reacting the free acid or base form of thesecompounds with a sufficient amount of the corresponding base or acid inwater or an organic solvent such as for example ether, ethyl acetate,ethanol, isopropanol, acetonitrile (or mixtures thereof).

Salts of acids other than those mentioned above, which are useful forexample for purifying or isolating the compounds from the reactionmixtures (e.g. trifluoroacetates), are also to be regarded as part ofthe invention.

In a representation such as for example

the letter A has the function of a ring designation in order to make iteasier, for example, to indicate the attachment of the ring in questionto other rings.

For bivalent groups in which it is crucial to determine which adjacentgroups they bind and with which valency, the corresponding bindingpartners are indicated in brackets, where necessary for clarificationpurposes, as in the following representations:

or (R²)—C(O)NH— or (R²)—NHC(O)—;

Groups or substituents are frequently selected from among a number ofalternative groups/substituents with a corresponding group designation(e.g. R^(a), R^(b) etc). If such a group is used repeatedly to define acompound according to the invention in different molecular parts, itmust always be borne in mind that the various uses are to be regarded astotally independent of one another.

By a therapeutically effective amount for the purposes of this inventionis meant a quantity of substance that is capable of obviating symptomsof illness or of preventing or alleviating these symptoms, or whichprolong the survival of a treated patient.

List of abbreviations ACN, CH₃CN acetonitrile Boc tert.butoxy carbonylDCM dichloromethane DIPEA diisopropylethyl amine DMAPdimethyl-pyridin-4-yl-amine DMF N,N-dimethylformamide DMSOdimethylsulphoxide EDTA ethylenediaminetetraacetic acid EtOAc or EAethyl acetate FCS Fetal calf serum h hour(s) HATUN-[(dimethylamino)-(1H-1,2,3-triazolo[4,5-b]pyridin-1-yl)-methylenel-N-methylmethan-aminium hexafluorophosphate N-oxide HPLChigh performance liquid chromatography KOAc potassium acetate LiHMDSlithium hexamethyl disilazide M Molar Min minute(s) mL Millilitre MSmass spectrometry N Normal NMR nuclear resonance spectroscopy PE petrolether PPh3 triphenylphosphine DIBAL diisobutylaluminium hydride RPreversed phase Rpm rounds per minute RT or rt room temperature STABSodium triacetoxy borohydride TBME tert.butyl methyl ether TEAtriethylamine tert tertiary TFA trifluoroacetic acid THF tetrahydrofurantR retention time [min] TRIS tris(hydroxymethyl)aminomethane wt % weightpercent sat. Saturated Ar aromatic

Other features and advantages of the present invention will becomeapparent from the following more detailed Examples which exemplarilyillustrate the principles of the invention without restricting itsscope.

GENERAL

Unless stated otherwise, all the reactions are carried out incommercially obtainable apparatus using methods that are commonly usedin chemical laboratories. Starting materials that are sensitive to airand/or moisture are stored under protective gas and correspondingreactions and manipulations therewith are carried out under protectivegas (nitrogen or argon).

The compounds are named according to the Beilstein rules using theAutonom software (Beilstein). If a compound is to be represented both bya structural formula and by its nomenclature, in the event of a conflictthe structural formula is decisive.

Chromatography

Thin layer chromatography is carried out on ready-made TLC plates ofsilica gel 60 on glass (with fluorescence indicator F-254) made byMerck.

The preparative high pressure chromatography (HPLC) of the examplecompounds according to the invention is carried out with columns made byWaters (names: Sunfire C18 OBD, 10 μm, 30×100 mm Part. No. 186003971;X-Bridge C18 OBD, 10 μm, 30×100 mm Part. No. 186003930). The compoundsare eluted using different gradients of H₂O/ACN wherein 0.2% HCOOH isadded to the water (acid conditions). For chromatography under basicconditions the water is made basic according to the following recipe: 5mL of ammonium hydrogen carbonate solution (158 g to 1 L H₂O) and 2 ml32% ammonia_((aq)) are made up to 1 L with H₂O.

The analytical HPLC (reaction monitoring) of intermediate compounds iscarried out with columns made by Waters and Phenomenex. The analyticalequipment is also provided with a mass detector in each case.

HPLC Mass Spectroscopy/UV Spectrometry

The retention times/MS-ESI⁺ for characterising the example compoundsaccording to the invention are produced using an HPLC-MS apparatus (highperformance liquid chromatography with mass detector) made by Agilent.Compounds that elute at the injection peak are given the retention timet_(Ret.)=0.

HPLC-Methods Preparative

prep. HPLC1

-   -   HPLC: 333 and 334 Pumps    -   Column: Waters X-Bridge C18 OBD, 10 μm, 30×100 mm, Part. No.        186003930    -   Solvent: A: 10 mM NH₄HCO₃ in H₂O; B: Acetonitril (HPLC grade)    -   Detection: UV/Vis-155    -   Flow: 50 ml/min

Gradient: 0.00-1.50 min: 1.5% B 1.50-7.50 min: varying 7.50-9.00 min:100% BPrep. HPLC2

-   -   HPLC: 333 and 334 Pumps    -   Column: Waters Sunfire C18 OBD, 10 μm, 30×100 mm, Part. No.        186003971    -   Solvent: A: H₂O+0.2% HCOOH; B: Acetonitril (HPLC grade)+0.2%        HCOOH    -   Detection: UV/Vis-155    -   Flow: 50 ml/min

Gradient: 0.00-1.50 min: 1.5% B 1.50-7.50 min: varying 7.50-9.00 min:100% B

HPLC-Methods Analytic LCMSBAS1

-   -   HPLC: Agilent 1100 Series    -   MS: Agilent LC/MSD SL    -   Column: Phenomenex Mercury Gemini C18, 3 μm, 2×20 mm, Part. No.        00M-4439-BO-CE    -   Solvent: A: 5 mM NH₄HCO₃/20 mM NH₃ in H₂O; B: Acetonitril (HPLC        grade)    -   Detection: MS: Positive and negative mode    -   Mass range: 120-900 m/z    -   Flow: 1.00 ml/min

Column temperature: 40° C.

Gradient: 0.00-2.50 min: 5% → 95% B 2.50-2.80 min: 95% B 2.81-3.10 min:95% → 5% B

FECB5

-   -   HPLC: Agilent 1100/1200 Series    -   MS: Agilent LC/MSD SL    -   Column: Waters X-Bridge C18 OBD, 5 μm, 2.1×50 mm    -   Solvent: A: 5 mM NH₄HCO₃/19 mM NH₃ in H₂O; B: Acetonitril (HPLC        grade)    -   Detection: MS: Positive and negative mode    -   Mass range: 105-1200 m/z    -   Flow: 1.20 ml/min    -   Column temperature: 35° C.

Gradient: 0.00-1.25 min: 5% → 95% B 1.25-2.00 min: 95% B 2.00-2.01 min:95% → 5% B

FECBM3ESI

-   -   HPLC: Agilent 1100/1200 Series    -   MS: Agilent LC/MSD SL    -   Column: Waters X-Bridge C18 OBD, 5 μm, 2.1×50 mm    -   Solvent: A: 5 mM NH₄HCO₃/19 mM NH₃ in H₂O; B: Acetonitril (HPLC        grade)    -   Detection: MS: Multimode ESI Positive and negative mode    -   Mass range: 105-1200 m/z    -   Flow: 1.20 ml/min    -   Column temperature: 35° C.

Gradient: 0.00-1.25 min: 5% → 100% B 1.25-2.00 min: 100% B 2.00-2.01min: 100% → 5% B

VAB

-   -   HPLC: Agilent 1100/1200 Series    -   MS: Agilent LC/MSD SL    -   Column: Waters X-Bridge BEH C18, 2.5 μm, 2.1×30 mm XP    -   Solvent: A: 5 mM NH₄HCO₃/19 mM NH₃ in H₂O; B: Acetonitril (HPLC        grade)    -   Detection: MS: Positive and negative mode    -   Mass range: 100-1200 m/z    -   Flow: 1.40 ml/min    -   Column temperature: 45° C.

Gradient: 0.00-1.00 min: 5% → 100% B 1.00-1.37 min: 100% B 1.37-1.40min: 100% → 5% B

FA-8

-   -   HPLC-MS: Waters—Alliance 2996    -   Column: Symmetryshield C18, 5 μm, 4.6×250 mm    -   Solvent: A: H₂O+0.1% TFA; B: Acetonitril (HPLC grade)    -   Detection: MS: Positive and negative mode    -   Mass range: 100-1200 m/z    -   Flow: 1.00 ml/min    -   Column temperature: 25° C.

Gradient:  2.00-8.00 min: 20% → 80% B  8.00-19.00 min: 80% B 19.00-20.00min: 80% → 20% B

FSUN2

-   -   HPLC: Agilent 1100/1200 Series    -   MS: Agilent LC/MSD SL    -   Column: Waters Sunfire C18, 5 μm, 2.1×50 mm    -   Solvent: A: H₂O+0.2% formic acid; B: Acetonitril (HPLC grade)    -   Detection: MS: Positive and negative mode    -   Mass range: 105-1200 m/z    -   Flow: 1.20 ml/min    -   Column temperature: 35° C.

Gradient: 0.0 min: 5% B  0.0-1.50 min: 5% → 95% B 1.50-2.00 min: 95% B2.00-2.01 min: 95% → 5% B

Preparation of the Compounds According to the Invention

The compounds according to the invention are prepared by the methods ofsynthesis described hereinafter, in which the substituents of thegeneral formula have the meanings given hereinbefore. These methods areintended as an illustration of the invention, without restricting itssubject matter and the scope of the compounds claimed to these examples.Where the preparation of starting compounds is not described, they arecommercially obtainable or may be prepared analogously to knowncompounds or methods described herein. Substances described in theliterature are prepared according to the published methods of synthesis.

Unless otherwise specified, the substituents R¹ through R³ of thefollowing reaction schemes are as defined in the description and claims.

The synthesis of key intermediate J from starting material A isillustrated in Scheme 1.

Starting from A, a nucleophilic aromatic substitution reaction can beused to introduce hydrazine B, which leads to C. Compound G can besynthesized applying an amidation reaction with D followed by abromation with F. After cleavage of the amide and ring closer with anorthoester derivative I the central intermediate J can be obtained.

The synthesis of compounds of formula I-III from key intermediate J isillustrated in Scheme 2.

Residue R2 can be introduced via a nucleophilic aromatic substitutionreaction using the corresponding amine, alcohol, thiol or a carbonucleophile (e.g. diethylmalonate) to produce intermediate K.

Final compounds I were synthesized starting from intermediate K andapplying a Suzuki reaction with boronic acids L.

Intermediate M, which is synthesized from K using a palladium catalyzedcarbonylation reaction, is the central intermediate for final compoundsII and III. Intermediate M was condensed with aromatic/heteroaromaticdiamines Q resulting in final compounds III.

Reduction of the acid of M and re oxidation of the corresponding alcohollead to intermediated N, which is condensed with oxime O and amine P tofinal compounds II.

Preparation of Intermediate J-16-bromo-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyrazine J-1

Reaction Scheme:

2-chloro-3-hydrazinylpyrazine C-1

2,3-Dichloropyrazine A-1 (15 g; 100.68 mmol) and hydrazine hydrate 65%(15.509 ml; 201.37 mmol) are dissolved in 45 ml ethanol and stirred for1 h at 80° C. While cooling down, a precipitate is formed. It is slurredup with a small amount of water and filtered off. It is washed withwater and then dried to afford the product.

Yield: 93% (13.6 g; 94.07 mmol)

HPLC-MS: (M+H)⁺=145/147; t_(Ret)=0.34 min; method FECB5

N′-(3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide E-1

2-Chloro-3-hydrazinylpyrazine C-1 (15.6 g; 108 mmol) is slurried up in(300 ml) THF and cooled down in an ice bath to −5° C. Trifluoroaceticanhydride (17 ml; 118 mmol) is also dissolved in 300 ml THF and droppedslowly to the first solution. After 1 h most of the THF is evaporated,than a small amount of water is added and the mixture is extracted withDCM. The organic phase is dried over MgSO4 and evaporated to dryness.

Yield: 100%

HPLC-MS: (M+H)⁺=241/243; t_(Ret)=1.31 min; method FSUN2

N′-(5-bromo-3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide G-1

N′-(3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide E-1 (19.5 g;81.1 mmol) is dissolved in 300 ml anhydrous DCM and cooled down to −40°C. Afterwards NBS (18.8 g; 105 mmol) is added and stirred for 1 hour.The solution is diluted with water and extracted with DCM. The organicphase is then purified with flash chromatography:cHex/(EtOAc/CH3COOH=9/1)=80%/20% to 70%/30% within 10 column volumes.

Yield: 11% (2.83 g; 8.859 mmol)

HPLC-MS: (M−H)⁻=317/319/321; t_(Ret)=1.79 min; method FSUN2

5-bromo-3-chloro-2-hydrazinylpyrazine H-1

N′-(5-bromo-3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide G-1(1.59 g; 4.97 mmol) is dissolved in 30 ml EtOH and treated with 3 mlconc. HCl. It is stirred for 2 hours at 100° C. The reaction mixture iscooled down, diluted with water and then the pH adjusted to 8 withsaturated NaHCO₃ solution. The water phase is extracted with EtOAc, theorganic layer dried over MgSO4 and evaporated to dryness.

Yield: 71% (945 mg; 3.51 mmol)

HPLC-MS: (M−H)⁻=221/223/225; t_(Ret)=1.32 min; method FECB5

6-bromo-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyrazine J-1

5-bromo-3-chloro-2-hydrazinylpyrazine H-1 (945 mg; 3.51 mmol) isdissolved in 12 ml trimethyl orthoacetate and heated up to 130° C. for 1hour. The solution is diluted with water and extracted with EtOAc. Theorganic phase is then purified with flash chromatography:cHex/EtOAc=70%/30% to 55%/45% within 10 column volumes.

Yield: 71% (824 mg; 3.33 mmol)

HPLC-MS: (M+H)+=247/249/251; t_(Ret)=1.23 min; method FECB5

Preparation of Intermediate K-1 tert-butyl4-({6-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl}amino)piperidine-1-carboxylat

6-bromo-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyrazine J-1 (3.24 g;13.1 mmol), 4-amino-1-boc-piperidine (5.24 g; 26.2 mmol) and hünigbase(2.44 ml; 14.4 mmol) are dissolved in 30 ml THF and are stirred for 16hours at 25° C. The reaction mixture is diluted with water and extractedwith EtOAc. The organic layer is separated and dried over MgSO4 andevaporated to dryness.

Yield: 98% (6.60 g; 12.8 mmol)

HPLC-MS: (M+H)⁺=411/413; t_(Ret)=0.88 min; method VAB

Preparation of Intermediate K-36-bromo-3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyrazine K-3

Caesiumcarbonate (7.25 g; 22.3 mmol) is suspended in 5 ml NMP. To thissuspension di-tert-butyl malonate (4.80 g; 22.3 mmol) is added and theresulting mixture is stirred for 30 min at 25° C. Finally6-bromo-8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyrazine J-1 (1.00 g;4.04 mmol) is added and the reaction mixture is stirred for 18 h at 25°C. The reaction mixture is treated with aqueous 1 N HCl until the pHvalue is below 5 and then extracted with DCM. The organic layer isseparated and dried over MgSO4 and is evaporated to dryness.

The crude intermediate is purified using reverse phase chromatography(method prep. HPLC2). The intermediate is dissolved in 5 ml DCM and 5 mlTFA and stirred for 16 h at 40° C. The reaction mixture is evaporatedand the crude product is purified using reverse phase chromatography(method prep. HPLC2).

Yield: 15% (138 mg; 0.61 mmol)

HPLC-MS: (M+H)⁺=227/229; t_(Ret)=0.47 min; method VAB

According to the procedures of K-1 and K-3 the intermediates K-2 aresynthesized.

MS (M + H)⁺; HPLC- # Structure t_(Ret.) HPLC [min] Method K-2

M + H = 242/244; t_(Ret.) = 0.59 VAB K-3

M + H = 227/229; t_(Ret.) = 0.47 VAB K-4

M + H = 256/258; t_(Ret.) = 0.64 VAB K-5

M + H = 270/272; t_(Ret.) = 0.69 VAB K-6

M + H = 298/300; VAB

Preparation of Intermediate M-18-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}amino)-3-methyl-[1,2,4]triazolo[4,3-a]pyrazine-6-carboxylicAcid M-1

tert-butyl4-({6-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl}amino)piperidine-1-carboxylatK-1 (1.85 g; 3.59 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichlormethane adduct (310 mg, 0.38 mmol) andtriethylamine (910 mg; 8.99 mmol) are dissolved in 10 ml methanol and 10ml NMP. The reaction mixture is stirred for 3 h at 70° C. and 2 bar COpressure. The reaction mixture is diluted with water and extracted withEtOAc. The organic layer is separated and dried over MgSO₄ andevaporated to dryness. The crude product is purified using method prep.HPLC1. This intermediate is dissolved in 20 ml THF and is treated with10 ml of a 1 N aqueous LiOH solution. After 1 h the reaction mixture isdiluted with water and extracted with DCM. The organic layer isseparated and dried over MgSO₄ and evaporated to dryness.

Yield: 72% (976 mg; 2.59 mmol)

HPLC-MS: (M−H)⁻=375; t_(Ret)=0.88 min; method FECB5

According to the procedures of M-1 the intermediates M-2 and M-3 aresynthesized.

MS (M + H)⁺; HPLC- # Structure t_(Ret.) HPLC [min] Method M-2

M + H = 208; t_(Ret.) = 0.0 VAB M-3

M + H = 193; t_(Ret.) = 0.0 VAB M-4

M + H = 222; t_(Ret.) = 0.0 VAB M-5

M + H = 236; t_(Ret.) = 0.0 VAB M-6

M + H = 264; t_(Ret.) = 0.0 VAB

Preparation of Intermediate L-1(1-methyl-5-phenoxy-1H-pyrazol-4-yl)boronic Acid

1-Methyl-5-phenoxy-1H-pyrazole-4-carboxylic Acid ethyl ester

Phenol (30.3 g; 322 mmol) is dissolved in DMA and K₂CO₃ (88.9 g; 643mmol) is added portion wise. It is stirred for 10 minutes, then5-Bromo-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (50.0 g; 215mmol) is dropped to the reaction mixture and heated up to 140° C. for 16hours. A 10% citric acid solution is added and extracted with DCM. Theorganic layer is washed with sodium bicarbonate and brine, then driedand purified through column chromatography.

Yield: 43% (22.5 g; 91.37 mmol)

HPLC-MS: (M+H)⁺=247; t_(Ret)=3.50 min; method LCMS FA-8

1-Methyl-5-phenoxy-1H-pyrazole-4-carboxylic acid

1-Methyl-5-phenoxy-1H-pyrazole-4-carboxylic acid ethyl ester (22.6 g;91.4 mmol) is dissolved in THF/MeOH (1/1) and LiOH in water (7.67 g; 183mmol) is added. After 16 hours at ambient temperature the reactionmixture is washed with EtOAc. The aqueous layer is acidified with 1 NHCl and extracted with EtOAc. The organic layer is dried and evaporated.

Yield: 80% (16.0 g; 73.3 mmol)

HPLC-MS: (M+H)⁺=219; t_(Ret)=2.88 min; method LCMS FA-8

1-Methyl-5-phenoxy-1H-pyrazol-4-ylamine

To a stirred mixture of 1-Methyl-5-phenoxy-1H-pyrazole-4-carboxylic acid(16.0 g; 73.3 mmol), t-BuOH (51.2 g; 691 mmol) in 1,4-dioxane underargon are added DIPEA (37.4 g; 290 mmol) and diphenylphosphoryl azide(41.6 g; 151 mmol). After 10 minutes at ambient temperature it is heatedup to 110° C. and stirred for 3 hours. The solvent is evaporated and thecrude material purified by column chromatography. This compound isdissolved in DCM and treated with 4 M HCl in 1,4-dioxane. It is stirredfor 2 days at ambient temperature. The solvent is evaporated and theresidue dissolved in water and washed with EtOAc. The aqueous layer isbasified with aqueous NaHCO₃ solution and is extracted with EtOAc. Theorganic layer is dried and concentrated to dryness.

Yield: 32% (16.0 g; 73.3 mmol)

HPLC-MS: (M+H)⁺=190; t_(Ret)=2.32 min; method LCMS FA-8

4-Iodo-1-methyl-5-phenoxy-1H-pyrazole

1-Methyl-5-phenoxy-1H-pyrazol-4-ylamine (4.50 g; 23.8 mmol) is dissolvedin H₂SO₄ and cooled to 0° C. NaNO₂ (1.64 g; 23.8 mmol) is dissolved inwater and is added to the reaction mixture. It is stirred for 1 hour at0° C. then KI (15.8 g; 95.1 mmol) is added whilst vigorous stirring andwarming up to ambient temperature within 30 minutes. It is treated withwater and neutralized with saturated NaHCO₃ solution. The water layer isextracted with DCM, dried and purified by column chromatography.

Yield: 38% (2.70 g; 8.99 mmol)

HPLC-MS: (M+H)⁺=301; t_(Ret)=3.74 min; method LCMS FA-8

(1-methyl-5-phenoxy-1H-pyrazol-4-yl)boronic Acid

4-Iodo-1-methyl-5-phenoxy-1H-pyrazole (862 mg; 2.75 mmol) is dissolvedin 15 ml THF extra dry and cooled down to −78° C. Afterwards n-BuLi(1.80 ml; 2.88 mmol; 1.6 mol/l in Hexane) and Triisopropyl borate(982.28 mg; 5.22 mmol) are added. It is stirred for 1 hour. The reactionmixture is quenched with 1 ml water and purified with reversed phasechromatography under basic conditions.

Yield: 67% (400 mg; 1.84 mmol)

HPLC-MS: (M+H)⁺=219; t_(Ret)=1.34 min; method FECB5

Preparation of Intermediate L-2(5-benzyl-1-methyl-1H-pyrazol-4-yl)boronic Acid

(4-Bromo-2-methyl-2H-pyrazol-3-yl)-phenyl-methanol

4-Bromo-2-methyl-2H-pyrazole-3-carbaldehyde (1.00 g; 5.29 mmol) isdissolved in 5.0 ml of anhydrous THF and cooled down to −78° C.Phenylmagnesium chloride 2 mol/l (6.61 ml; 13.2 mmol) is added and thereaction mixture is stirred for 1 hour. It is warmed up to 0° C. and isquenched carefully with water, then extracted with DCM. The organiclayers are pooled, dried over MgSO₄ and purified by using reversed phasechromatography under basic conditions.

Yield: 82% (1.16 g; 4.35 mmol)

HPLC-MS: (M+H)⁺=267; t_(Ret)=1.59 min; method FECBM3ESI

5-Benzyl-4-bromo-1-methyl-1H-pyrazole

(4-Bromo-2-methyl-2H-pyrazol-3-yl)-phenyl-methanol (0.50 g; 1.87 mmol)is treated with 3.0 ml TFA and Triethylsilane (1.49 ml; 9.36 mmol) andis heated to 50° C. for 16 hours. The product is purified via reversedphase chromatography under acid conditions.

Yield: 56% (0.26 g; 1.06 mmol)

HPLC-MS: (M+H)+=251/253; t_(Ret)=1.71 min; method FECBM3ESI

(5-benzyl-1-methyl-1H-pyrazol-4-yl)boronic Acid

5-Benzyl-4-bromo-1-methyl-1H-pyrazole (0.27 g; 1.06 mmol) is dissolvedin 5.0 ml anhydrous THF and cooled down to −78° C. Afterwardstriisopropyl borate (0.46 ml; 2.01 mmol) and n-BuLi; 1.6 mol/l inHexane; (0.69 ml; 1.11 mmol) are added. It is stirred for 1 hour withinthe desired product is formed. It is warmed to 25° C. and quenched withwater. It is purified with reverse phase chromatography by using basicconditions.

Yield: 39% (0.08 g; 0.41 mmol)

HPLC-MS: (M+H)⁺=217; t_(Ret)=1.41 min; method FECBM3ESI

Preparation of Intermediate L-5(5-benzyl-1-methyl-1H-pyrazol-4-yl)boronic Acid—L-5

Reaction Scheme:

Intermediate L-5-4 is synthesized according to the procedures describedin Bioorganic & Med. Chem. Letters 18(2) 509-512 2008. For the synthesisof the boronic acid L-5 the procedures described for L-1 and L-2 areused.

HPLC-MS: (M+H)⁺=233; t_(Ret)=0.73 min; method VAB

According to the procedures of L-1 and L-2 the intermediates L-3 and L-4are synthesized.

MS (M + H)⁺; r_(Ret.) HPLC # Structure [min] HPLC-Method L-3

M + H = 217; t_(Ret.) = 0.60 VAB L-4

M + H = 231; t_(Ret.) = 0.76 VAB

General Method for Preparation of Compounds of Formula I6-(3-benzyl-1-methyl-1H-pyrazol-4-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amineI-1

Intermediate G-2 (32 mg; 0.13 mmol), boronic acid L-3 (30 mg; 0.13mmol), Cs₂CO₃ 70% solution in water (0.05 ml; 0.25 mmol) andPd[P(t-Bu)₃]2 (5 mg; 0.01 mmol) are suspended with THF/NMP=2/1 (0.3 ml)and flushed with argon. It is stirred at 90° C. for 1 hour. The crudereaction mixture is purified by using reversed phase chromatographyunder acid conditions (Method: prep. HPLC2).

Yield: 33% (0.02 g; 0.04 mmol)

HPLC-MS: (M+H)⁺=417; t_(Ret)=1.05 min; method LCMSBAS1

According to I-1 the following examples are synthesized.

MS (M + H)⁺; t_(Ret.) HPLC HPLC- # Structure [min] Method I-1

M + H = 333; t_(Ret.) = 1.06 LCMSBAS1 I-2

M + H = 335; t_(Ret.) = 1.07 LCMSBAS1 I-3

M + H = 321; t_(Ret.) = 1.09 LCMSBAS1 I-4

M + H = 347; t_(Ret.) = 1.11 LCMSBAS1 I-5

M + H = 349; t_(Ret.) = 1.12 LCMSBAS1

General Method for Preparation of Compounds of Formula II6-(1-benzyl-5-methyl-4-phenyl-1H-imidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amineII-1

3-methyl-8-(methylamino)-[1,2,4]triazolo[4,3-a]pyrazine-6-carbaldehyde

3-methyl-8-(methylamino)-[1,2,4]triazolo[4,3-a]pyrazine-6-carboxylicacid M-2 (300 mg; 1.45 mmol) is dissolved in 2 ml THF and is treatedwith 1 M borane-THF complex (4 ml; 4.00 mmol). The reaction mixture isstirred for 16 h at 50° C. Afterwards the reaction mixture is cool downto 0° C. and 1 N aqueous HCl is added until the pH values is less than7.

It is diluted with DCM, the organic lays is separated and dried overMgSO₄. The crude product is purified by using reversed phasechromatography (Method: prep. HPLC1). This intermediate is suspended in20 ml Chloroform and treated with manganese dioxide (350 mg; 4.07 mmol).The reaction mixture is stirred for 4 days at 50° C. Afterwards thesolid material is filtered off and the solvent is evaporated.

Yield: 16% (44 mg; 0.23 mmol)

HPLC-MS: (M+H)⁺=192; t_(Ret)=0.52 min; method FECB5

6-(1-benzyl-5-methyl-4-phenyl-1H-imidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amineII-1

3-Methyl-8-methylamino-[1,2,4]triazolo[4,3-a]pyrazine-6-carbaldehyde (34mg; 0.18 mmol), benzylamine (20 μl; 0.18 mmol) and1-hydroxyimino-1-phenyl-propan-2-one (32 mg; 0.18 mmol) are dissolved in0.6 ml acetic acid stirred for 2 h at 120° C. The reaction mixture istreated with water and extracted with DCM. The organic layer is driedover MgSO4 and evaporated to dryness. The crude intermediate isdissolved in 20 ml of THF and treated with Ra—Ni. The reaction mixtureis stirred for 2 days at 25° C. and 4 bar hydrogen atmosphere. The solidmaterials are filtered off and the crude product is purified usingreversed phase chromatography (Method: prep. HPLC1).

Yield: 33% (25 mg; 0.06 mmol)

HPLC-MS: (M+H)⁺=410; t_(Ret)=1.17 min; method LCMSBAS1

According to II-1 the following examples are synthesized.

MS (M + H)⁺; # Structure t_(Ret.) HPLC [min] HPLC-Method II-1

M + H = 410; t_(Ret.) = 1.17 LCMSBAS1 II-2

M + H = 348; t_(Ret.) = 1.09 LCMSBAS1 II-3

M + H = 333; t_(Ret.) = 1.11 LCMSBAS1

Preparation of Intermediate Q-6N-4-Benzyl-6-(4-methyl-piperazin-1-yl)-pyridine-3,4-diamine Q-6

2,4-Dichloro-5-nitro-pyridine (250 mg; 1.29 mmol), benzylamine (153 μl;1.42 mmol) and DIPEA (314 μl; 1.94 mmol) are suspended in 1 ml NMP andstirred for 1 h at 25° C. To this suspension 1-methylpiperazine (159 μl;1.43 mmol) is added and the resulting mixture is stirred for 16 h at 50°C. The crude intermediate is purified using reversed phasechromatography (prep. HPLC). This intermediate is dissolved in 30 ml THFand palladium on carbon is added. The reaction mixture is stirred for 3h at 25° C. and 4 bar hydrogen pressure. The solid material is filteredoff and the solvent is evaporated.

Yield: 48% (184 mg; 0.62 mmol)

HPLC-MS: (M+H)⁺=298; t_(Ret)=0.68 min; method VAB

Preparation of Intermediate Q-296-(propan-2-yl)-4-N-(pyridin-2-ylmethyl)pyridine-3,4-diamine

2,4-Dichloro-5-nitro-pyridine (500 mg; 2.46 mmol),pyridine-2-yl-methylamine (260 μl; 2.49 mmol) and triethylamine (400 μl;2.82 mmol) are suspended in 1 ml NMP and stirred for 1 h at 25° C. Thereaction mixture is diluted with water and the precipitate is filteredoff, washed with water and methanol and dried.

Yield: 87% (566 mg; 2.14 mmol)

This intermediate (125 mg, 0.47 mmol),2-Isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (200 μl; 1.06mmol), Cs₂CO₃ (300 mg; 0.90 mmol) and Pd DPPF (30 mg; 0.04 mmol) aresuspended with 1,2dimethoxyethane/water=3/1 (10 ml) and flushed withargon. It is stirred at 95° C. for 1 hour. The crude reaction mixture ispurified by using reversed phase chromatography under basic conditions(Method: prep. HPLC1).

Yield: 43% (55 mg; 0.20 mmol)

This intermediate (40 mg, 0.15 mmol) is dissolved in 10 ml methanol andpalladium on carbon is added. The reaction mixture is stirred for 3 h at25° C. and 4 bar hydrogen pressure. The solid material is filtered offand the solvent is evaporated.

Yield: 95% (35 mg; 0.14 mmol)

HPLC-MS: (M+H)⁺=242; t_(Ret)=0.68 min; method VAB

According to the procedures of Q-6 and Q-29 the intermediates Q-1-Q-39are synthesized.

MS (M + H)⁺; HPLC- # Structure t_(Ret.) HPLC [min] Method Q-1

commercial available Q-2

M + H = 213; t_(Ret.) = 1.96 FECB5 Q-3

M + H = 213; t_(Ret.) = 1.96 FECB5 Q-4

M + H = 217; t_(Ret.) = 0.87 VAB Q-5

M + H = 235; t_(Ret.) = 0.89 VAB Q-6

M + H = 298; t_(Ret.) = 0.68 VAB Q-7

M + H = 200; t_(Ret.) = 0.69 VAB Q-8

M + H = 299; t_(Ret.) = 0.71 VAB Q-9

M + H = 284; t_(Ret.) = 0.76 VAB Q-10

M + H = 297; t_(Ret.) = 1.54 FECB5 Q-11

M + H = 309; t_(Ret.) = 1.63 FECB5 Q-12

M + H = 313; t_(Ret.) = 0.80 VAB Q-13

M + H = 299; t_(Ret.) = 1.30 FECB5 Q-14

M + H = 286; t_(Ret.) = 0.56 VAB Q-15

M + H = 285; t_(Ret.) = 0.78 VAB Q-16

M + H = 284; t_(Ret.) = 0.72 VAB Q-17

M + H = 304; t_(Ret.) = 0.63 VAB Q-18

M + H = 300; t_(Ret.) = 0.66 VAB Q-19

M + H = 300; t_(Ret.) = 0.66 VAB Q-20

M + H = 244; t_(Ret.) = 0.59 VAB Q-21

M + H = 243; t_(Ret.) = 0.77 VAB Q-22

M + H = 200; t_(Ret.) = 0.70 VAB Q-23

M + H = 230; t_(Ret.) = 1.44 FECB5 Q-24

M + H = 214; t_(Ret.) = 0.76 VAB Q-25

M + H = 215; t_(Ret.) = 0.20 VAB Q-26

M + H = 201; t_(Ret.) = 0.52 VAB Q-27

M + H = 300; t_(Ret.) = 0.63 VAB Q-28

M + H = 231; t_(Ret.) = 0.62 VAB Q-29

M + H = 243; t_(Ret.) = 0.68 VAB Q-30

M + H = 314; t_(Ret.) = 1.40 FECB5 Q-31

M + H = 257; t_(Ret.) = 0.72 VAB Q-32

M + H = 285; t_(Ret.) = 0.54 VAB Q-33

M + H = 284; t_(Ret.) = 0.73 VAB Q-34

M + H = 298; t_(Ret.) = 0.76 VAB Q-35

M + H = 256; t_(Ret.) = 0.89 VAB Q-36

M + H = 299; t_(Ret.) = 1.26 FECB5 Q-37

M + H = 298; t_(Ret.) = 0.57 VAB Q-36

M + H = 286; t_(Ret.) = 0.54 VAB Q-37

M + H = 285; t_(Ret.) = 0.59 VAB Q-38

M + H = 215; t_(Ret.) = 1.25 FECB5 Q-39

M + H = 299; t_(Ret.) = 0.55 VAB

General Method for Preparation of Compounds of Formula IIIN-[6-(1-benzyl-1H-1,3-benzodiazol-2-yl)-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl]-1-methylpiperidin-4-amineIII-1

N-[6-(1-benzyl-1H-1,3-benzodiazol-2-yl)-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl]piperidin-4-amine

8-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}amino)-3-methyl-[1,2,4]triazolo[4,3-a]pyrazine-6-carboxylicacid M-1 (238 mg; 0.63 mmol), Hünigbase (306 μl; 1.89 mmol) and HATU(264 mg; 0.69 mmol) are dissolved in 2 ml DMF. The reaction mixture isstirred for 10 min, then N-benzyl-1,2-diaminobenzene Q-1 (138 mg; 0.69mmol) is added and the resulting mixture is stirred for an additional 1h at 25° C. The reaction mixture is diluted with water and DCM. Theorganic layer is separated and dried over MgSO₄ and the solvent isevaporated. The crude intermediate is dissolved in 4 ml acetic acid andstirred at 100° C. for 3 h. Afterwards the reaction mixture isneutralized with aqueous NaHCO₃ solution and extracted with DCM. Thecrude intermediate is dissolved in 10 ml DCM and 10 ml TFA and stirredfor 1 h at 25° C. Afterwards the reaction mixture is neutralized withaqueous NaHCO₃ solution and extracted with DCM. The organic layer isseparated and dried over MgSO₄ and the solvent is evaporated. The crudeproduct is purified using reversed phase chromatography (Method: prep.HPLC1).

Yield: 33% (93 mg; 0.21 mmol)

HPLC-MS: (M+H)⁺=439; t_(Ret)=0.77 min; method VAB

N-[6-(1-benzyl-1H-1,3-benzodiazol-2-yl)-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl]-1-methylpiperidin-4-amine

N-[6-(1-benzyl-1H-1,3-benzodiazol-2-yl)-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl]piperidin-4-amine(93 mg; 0.21 mmol) is dissolved in 300 μl THF, treated with DIPEA (62μl; 0.29 mmol) and formaldehyde (62 al; 0.83 mmol). To this reactionmixture STAB (62 mg; 0.29 mmol) is added and the reaction mixture isstirred for 2 hours. The crude reaction mixture is purified by reversedphase chromatograph (Method: prep. HPLC1).

Yield: 60% (58 mg; 0.13 mmol)

HPLC-MS: (M+H)⁺=453; t_(Ret)=1.19 min; method LCMSBAS1

According to III-1 the following examples are synthesized.

MS (M + H)⁺; HPLC- # Structure t_(Ret). HPLC [min] Method III-1 

M + H = 453; t_(Ret.) = 1.19 LCMSBAS1 III-2 

M + H = 511; t_(Ret.) = 1.23 LCMSBAS1 III-3 

M + H = 511; t_(Ret.) = 1.23 LCMSBAS1 III-4 

M + H = 497; t_(Ret.) = 1.19 LCMSBAS1 III-5 

M + H = 515; t_(Ret.) = 1.2 LCMSBAS1 III-6 

M + H = 533; t_(Ret.) = 1.22 LCMSBAS1 III-7 

M + H = 370; t_(Ret.) = 1.14 LCMSBAS1 III-8 

M + H = 469; t_(Ret.) = 1.01 LCMSBAS1 III-9 

M + H = 454; t_(Ret.) = 1.03 LCMSBAS1 III-10

M + H = 371; t_(Ret.) = 1.03 LCMSBAS1 III-11

M + H = 470; t_(Ret.) = 1.08 LCMSBAS1 III-12

M + H = 582; t_(Ret.) = 1.1 LCMSBAS1 III-13

M + H = 468; t_(Ret.) = 1.06 LCMSBAS1 III-14

M + H = 455; t_(Ret.) = 1.07 LCMSBAS1 III-15

M + H = 607; t_(Ret.) = 1.04 LCMSBAS1 III-16

M + H = 480; t_(Ret.) = 1.01 LCMSBAS1 III-17

M + H = 483; t_(Ret.) = 0.77 VAB III-18

M + H = 497; t_(Ret.) = 0.82 VAB III-19

M + H = 512; t_(Ret.) = 1.23 LCMSBAS1 III-20

M + H = 470; t_(Ret.) = 0.84 LCMSBAS1 III-21

M + H = 469; t_(Ret.) = 0.88 LCMSBAS1 III-22

M + H = 457; t_(Ret.) = 0.84 LCMSBAS1 III-23

M + H = 456; t_(Ret.) = 0.88 LCMSBAS1 III-24

M + H = 513; t_(Ret.) = 0.86 LCMSBAS1 III-25

M + H = 455; t_(Ret.) = 0.99 LCMSBAS1 III-26

M + H = 484; t_(Ret.) = 0.99 LCMSBAS1 III-27

M + H = 485; t_(Ret.) = 0.95 LCMSBAS1 III-28

M + H = 503; t_(Ret.) = 1.02 LCMSBAS1 III-29

M + H = 499; t_(Ret.) = 1.01 LCMSBAS1 III-30

M + H = 499; t_(Ret.) = 1.01 LCMSBAS1 III-31

M + H = 443; t_(Ret.) = 1.02 LCMSBAS1 III-32

M + H = 442; t_(Ret.) = 1.10 LCMSBAS1 III-33

M + H = 399; t_(Ret.) = 1.06 LCMSBAS1 III-34

M + H = 429; t_(Ret.) = 1.06 LCMSBAS1 III-35

M + H = 413; t_(Ret.) = 1.13 LCMSBAS1 III-36

M + H = 414; t_(Ret.) = 0.92 LCMSBAS1 III-37

M + H = 400; t_(Ret.) = 0.87 LCMSBAS1 III-38

M + H = 499; t_(Ret.) = 1.02 LCMSBAS1 III-39

M + H = 430; t_(Ret.) = 0.99 LCMSBAS1 III-40

M + H = 442; t_(Ret.) = 1.08 LCMSBAS1 III-41

M + H = 513; t_(Ret.) = 1.09 LCMSBAS1 III-42

M + H = 456; t_(Ret.) = 1.17 LCMSBAS1 III-43

M + H = 484; t_(Ret.) = 0.97 LCMSBAS1 III-44

M + H = 483; t_(Ret.) = 1.10 LCMSBAS1 III-45

M + H = 497; t_(Ret.) = 1.16 LCMSBAS1 III-46

M + H = 455; t_(Ret.) = 1.35 LCMSBAS1 III-47

M + H = 470; t_(Ret.) = 0.81 LCMSBAS1 III-48

M + H = 469; t_(Ret.) = 0.85 LCMSBAS1 III-49

M + H = 457; t_(Ret.) = 0.81 LCMSBAS1 III-50

M + H = 456; t_(Ret.) = 0.86 LCMSBAS1 III-51

M + H = 513; t_(Ret.) = 0.82 LCMSBAS1 III-52

M + H = 442; t_(Ret.) = 0.77 LCMSBAS1 III-53

M + H = 470; t_(Ret.) = 0.81 LCMSBAS1

Biological Methods BRD4-H4 Tetraacetylated Peptide InhibitionAlphaScreen

This assay is used to determine whether the compounds inhibit theinteraction between the first (BRD4-BD1) or the second (BRD4-BD2)bromodomain of BRD4 and the tetraacetylated histone H4 peptide.

Compounds are diluted in serial dilution 1:5 in assay buffer from 10 mMstock in DMSO (100 μM start concentration) in white OptiPlate-384(PerkinElmer). A mix consisting of 15 nM GST-BRD4-BD1 protein (aa44-168) or 150 nM GST-BRD4-BD2 (aa 333-460) and 15 nM biotinylatedAcetyl-Histone H4 (Lys5, 8, 12, 16) peptide is prepared in assay buffer(50 mM HEPES pH=7.4; 25 mM NaCl; 0.05% Tween 20; 0.1% bovine serumalbumin (BSA); 10 mM dithiothreitol (DTT)). 6 μl of the mix is added tothe compound dilutions. Subsequently, 6 al of premixed AlphaLISAGlutathione Acceptor Beads and AlphaScreen Streptavidin Donor Beads fromPerkinElmer (in assay buffer at a concentration of 10 jag/ml each) areadded and the samples are incubated for 30 min at RT in the dark(shaking 300 rpm). Afterwards, the signal is measured in a PerkinElmerEnvision HTS Multilabel Reader using the AlphaScreen protocol fromPerkinElmer.

Each plate contains negative controls where biotinylated Acetyl-HistoneH4 peptide and GST-BRD4-BD1 or GST-BRD4-BD2 are left out and replaced byassay buffer. Negative control values are entered as low basis valuewhen using the software GraphPad Prism for calculations. Furthermore, apositive control (probe molecule JQ1+ with protein/peptide mix) ispipetted. Determination of IC₅₀ values are carried out using GraphPadPrism 3.03 software (or updates thereof).

Table Summarizing the IC₅₀ of the Compounds of the Invention ExemplifiedAbove

BRD4-BD1 Ex # IC₅₀ [nM] I-1 61 I-2 41 I-3 41 I-4 18 I-5 8 II-1 4 II-2 15II-3 31 III-1  7 III-2  41 III-3  49 III-4  8 III-5  9 III-6  9 III-7 22 III-8  9 III-9  14 III-10 18 III-11 9 III-12 7 III-13 9 III-14 10III-15 3 III-16 5 III-17 17 III-18 26 III-19 38 III-20 13 III-21 8III-22 3 III-23 3 III-24 20 III-25 11 III-26 5 III-27 10 III-28 1 III-299 III-30 9 III-31 13 III-32 7 III-33 20 III-34 45 III-35 15 III-36 28III-37 14 III-38 17 III-39 126 III-40 18 III-41 74 III-42 66 III-43 34III-44 32 III-45 69 III-46 243 III-47 12 III-48 8 III-49 4 III-50 5III-51 13 III-52 31 III-53 12

On the basis of their biological properties the compounds of generalformula (1) according to the invention, their tautomers, racemates,enantiomers, diastereomers, mixtures thereof and the salts of all theabove-mentioned forms are suitable for treating diseases characterisedby virus infection, inflammatory diseases and abnormal cellproliferation, such as cancer.

For example, the following cancers may be treated with compoundsaccording to the invention, without being restricted thereto: braintumours such as for example acoustic neurinoma, astrocytomas such aspilocytic astrocytomas, fibrillary astrocytoma, protoplasmicastrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma andglioblastoma, brain lymphomas, brain metastases, hypophyseal tumour suchas prolactinoma, HGH (human growth hormone) producing tumour and ACTHproducing tumour (adrenocorticotropic hormone), craniopharyngiomas,medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours(neoplasms) such as for example tumours of the vegetative nervous systemsuch as neuroblastoma sympathicum, ganglioneuroma, paraganglioma(pheochromocytoma, chromaffinoma) and glomus-caroticum tumour, tumourson the peripheral nervous system such as amputation neuroma,neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignantSchwannoma, as well as tumours of the central nervous system such asbrain and bone marrow tumours; intestinal cancer such as for examplecarcinoma of the rectum, colon carcinoma, colorectal carcinoma, analcarcinoma, carcinoma of the large bowel, tumours of the small intestineand duodenum; eyelid tumours such as basalioma or basal cell carcinoma;pancreatic cancer or carcinoma of the pancreas; bladder cancer orcarcinoma of the bladder; lung cancer (bronchial carcinoma) such as forexample small-cell bronchial carcinomas (oat cell carcinomas) andnon-small cell bronchial carcinomas (NSCLC) such as plate epithelialcarcinomas, adenocarcinomas and large-cell bronchial carcinomas; breastcancer such as for example mammary carcinoma such as infiltrating ductalcarcinoma, colloid carcinoma, lobular invasive carcinoma, tubularcarcinoma, adenocystic carcinoma and papillary carcinoma; non-Hodgkin'slymphomas (NHL) such as for example Burkitt's lymphoma, low-malignancynon-Hodgkin's lymphomas (NHL) and mucosis fungoides; uterine cancer orendometrial carcinoma or corpus carcinoma; CUP syndrome (Cancer ofUnknown Primary); ovarian cancer or ovarian carcinoma such as mucinous,endometrial or serous cancer; gall bladder cancer; bile duct cancer suchas for example Klatskin tumour; testicular cancer such as for exampleseminomas and non-seminomas; lymphoma (lymphosarcoma) such as forexample malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas(NHL) such as chronic lymphatic leukaemia, leukaemicreticuloendotheliosis, immunocytoma, plasmocytoma (multiple myeloma(MM)), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides,large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngealcancer such as for example tumours of the vocal cords, supraglottal,glottal and subglottal laryngeal tumours; bone cancer such as forexample osteochondroma, chondroma, chondroblastoma, chondromyxoidfibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilicgranuloma, giant cell tumour, chondrosarcoma, osteosarcoma, Ewing'ssarcoma, reticulo-sarcoma, plasmocytoma, fibrous dysplasia, juvenilebone cysts and aneurysmatic bone cysts; head and neck tumours such asfor example tumours of the lips, tongue, floor of the mouth, oralcavity, gums, palate, salivary glands, throat, nasal cavity, paranasalsinuses, larynx and middle ear; liver cancer such as for example livercell carcinoma or hepatocellular carcinoma (HCC); leukaemias, such asfor example acute leukaemias such as acute lymphatic/lymphoblasticleukaemia (ALL), acute myeloid leukaemia (AML); chronic leukaemias suchas chronic lymphatic leukaemia (CLL), chronic myeloid leukaemia (CML);stomach cancer or gastric carcinoma such as for example papillary,tubular and mucinous adenocarcinoma, signet ring cell carcinoma,adenosquamous carcinoma, small-cell carcinoma and undifferentiatedcarcinoma; melanomas such as for example superficially spreading,nodular, lentigo-maligna and acral-lentiginous melanoma; renal cancersuch as for example kidney cell carcinoma or hypernephroma or Grawitz'stumour; oesophageal cancer or carcinoma of the oesophagus; penilecancer; prostate cancer; throat cancer or carcinomas of the pharynx suchas for example nasopharynx carcinomas, oropharynx carcinomas andhypopharynx carcinomas; retinoblastoma such as for example vaginalcancer or vaginal carcinoma; plate epithelial carcinomas,adenocarcinomas, in situ carcinomas, malignant melanomas and sarcomas;thyroid carcinomas such as for example papillary, follicular andmedullary thyroid carcinoma, as well as anaplastic carcinomas;spinalioma, epidormoid carcinoma and plate epithelial carcinoma of theskin; thymomas, cancer of the urethra and cancer of the vulva.

Preferred cancers, which may be treated with compounds according to theinvention, are hematopoietic malignancies (including but not limited toAML, MM), as well as solid tumors including but not limited to lung,liver, colon, brain, thyroid, pancreas, breast, ovary and prostatecancer.

The new compounds may be used for the prevention, short-term orlong-term treatment of the above-mentioned diseases, optionally also incombination with radiotherapy or other “state-of-the-art” compounds,such as e.g. cytostatic or cytotoxic substances, cell proliferationinhibitors, anti-angiogenic substances, steroids or antibodies.

The compounds of general formula (I) may be used on their own or incombination with other active substances according to the invention,optionally also in combination with other pharmacologically activesubstances.

Chemotherapeutic agents which may be administered in combination withthe compounds according to the invention, include, without beingrestricted thereto, hormones, hormone analogues and antihormones (e.g.tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate,flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproteroneacetate, finasteride, buserelin acetate, fludrocortisone,fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors(e.g. anastrozole, letrozole, liarozole, vorozole, exemestane,atamestane), LHRH agonists and antagonists (e.g. goserelin acetate,luprolide), inhibitors of growth factors (growth factors such as forexample “platelet derived growth factor” and “hepatocyte growth factor”,inhibitors are for example “growth factor” antibodies, “growth factorreceptor” antibodies and tyrosine kinase inhibitors, such as for examplecetuximab, gefitinib, imatinib, lapatinib and trastuzumab);antimetabolites (e.g. antifolates such as methotrexate, raltitrexed,pyrimidine analogues such as 5-fluorouracil, capecitabin and gemcitabin,purine and adenosine analogues such as mercaptopurine, thioguanine,cladribine and pentostatin, cytarabine, fludarabine); antitumourantibiotics (e.g. anthracyclins such as doxorubicin, daunorubicin,epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin,plicamycin, streptozocin); platinum derivatives (e.g. cisplatin,oxaliplatin, carboplatin); alkylation agents (e.g. estramustin,meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin,cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as forexample carmustin and lomustin, thiotepa); antimitotic agents (e.g.Vinca alkaloids such as for example vinblastine, vindesin, vinorelbinand vincristine; and taxanes such as paclitaxel, docetaxel);topoisomerase inhibitors (e.g. epipodophyllotoxins such as for exampleetoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan,mitoxantron) and various chemotherapeutic agents such as amifostin,anagrelid, clodronat, filgrastin, interferon alpha, leucovorin,rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate andporfimer.

Other possible combination partners are 2-chlorodesoxyadenosine,2-fluorodesoxycytidine, 2-methoxyoestradiol, 2C4, 3-alethine,131-I-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B,A 105972, A 204197, aldesleukin, alitretinoin, altretamine, alvocidib,amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine,aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE,AVLB, AZ10992, ABX-EGF, ARRY-300, ARRY-142886/AZD-6244,ARRY-704/AZD-8330, AS-703026, azacytidine, azaepothilone B, azonafide,BAY-43-9006, BBR-3464, BBR-3576, bevacizumab, biricodar dicitrate,BCX-1777, bleocin, BLP-25, BMS-184476, BMS-247550, BMS-188797,BMS-275291, BNP-1350, BNP-7787, BIBW 2992(afatinib), BIBF 1120(Vargatef™), bleomycinic acid, bleomycin A, bleomycin B, bryostatin-1,bortezomib, brostallicin, busulphan, CA-4 prodrug, CA-4, CapCell,calcitriol, canertinib, canfosfamide, capecitabine,carboxyphthalatoplatin, CCI-779, CEP-701, CEP-751, CBT-1 cefixime,ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin,CH4987655/RO-4987655, chlorotrianisene, cilengitide, ciclosporin,CDA-II, CDC-394, CKD-602, clofarabin, colchicin, combretastatin A4,CHS-828, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CP-461, CV-247,cyanomorpholinodoxorubicin, cytarabine, D 24851, decitabine,deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide,desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol,diflomotecan, didox, DMDC, dolastatin 10, doranidazole, E7010, E-6201,edatrexat, edotreotide, efaproxiral, eflornithine, EKB-569, EKB-509,elsamitrucin, epothilone B, epratuzumab, ER-86526, erlotinib,ET-18-OCH3, ethynylcytidine, ethynyloestradiol, exatecan, exatecanmesylate, exemestane, exisulind, fenretinide, floxuridine, folic acid,FOLFOX, FOLFIRI, formestane, galarubicin, gallium maltolate, gefinitib,gemtuzumab, gimatecan, glufosfamide, GCS-IOO, G17DT immunogen, GMK,GPX-100, GSK-5126766, GSK-1120212, GW2016, granisetron,hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid,hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibritumomab,idatrexate, idenestrol, IDN-5109, IMC-1C11, immunol, indisulam,interferon alpha-2a, interferon alfa-2b, interleukin-2, ionafarnib,iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin,ixabepilone, JRX-2, JSF-154, J-107088, conjugated oestrogens, kahalid F,ketoconazole, KW-2170, lobaplatin, leflunomide, lenograstim, leuprolide,leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin,lometrexol, losoxantrone, LU 223651, lurtotecan, mafosfamide,marimastat, mechloroethamine, methyltestosteron, methylprednisolone,MEN-10755, MDX-H210, MDX-447, MGV, midostaurin, minodronic acid,mitomycin, mivobulin, MK-2206, MLN518, motexafin gadolinium, MS-209,MS-275, MX6, neridronate, neovastat, nimesulide, nitroglycerin,nolatrexed, norelin, N-acetylcysteine, 06-benzylguanine, omeprazole,oncophage, ormiplatin, ortataxel, oxantrazole, oestrogen, patupilone,pegfilgrastim, PCK-3145, pegfilgrastim, PBI-1402, PEG-paclitaxel,PEP-005, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix,perifosine, perillylalcohol, PG-TXL, PG2, PLX-4032/RO-5185426, PT-100,picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol 0,PK1166, plevitrexed, plicamycin, polyprenic acid, porfiromycin,prednisone, prednisolone, quinamed, quinupristin, RAF-265, ramosetron,ranpirnase, RDEA-119/BAY 869766, rebeccamycin analogues, revimid,RG-7167, rhizoxin, rhu-MAb, risedronate, rituximab, rofecoxib,Ro-31-7453, RO-5126766, RPR 109881A, rubidazon, rubitecan,R-flurbiprofen, S-9788, sabarubicin, SAHA, sargramostim, satraplatin, SB408075, SU5416, SU6668, SDX-101, semustin, seocalcitol, SM-11355, SN-38,SN-4071, SR-27897, SR-31747, SRL-172, sorafenib, spiroplatin,squalamine, suberanilohydroxamic acid, sutent, T 900607, T 138067,TAS-103, tacedinaline, talaporfin, tariquitar, taxotere, taxoprexin,tazarotene, tegafur, temozolamide, tesmilifene, testosterone,testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin,tezacitabine, thalidomide, theralux, therarubicin, thymectacin,tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, toremofin,trabectedin, TransMID-107, transretinic acid, traszutumab, tretinoin,triacetyluridine, triapine, trimetrexate, TLK-286TXD 258, urocidin,valrubicin, vatalanib, vincristine, vinflunine, virulizin, WX-UK1,vectibix, Volasertib (or other polo-like kinae inhibitors), xeloda,XELOX, XL-281, XL-518/R-7420, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054,ZD-0473, ZD-6126, ZD-9331, ZDI839, zoledronat and zosuquidar.

Suitable preparations include for example tablets, capsules,suppositories, solutions—particularly solutions for injection (s.c.,i.v., i.m.) and infusion—elixirs, emulsions or dispersible powders. Thecontent of the pharmaceutically active compound(s) should be in therange from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of thecomposition as a whole, i.e. in amounts which are sufficient to achievethe dosage range specified below. The doses specified may, if necessary,be given several times a day.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g.with the addition of isotonic agents, preservatives such asp-hydroxybenzoates, or stabilisers such as alkali metal salts ofethylenediamine tetraacetic acid, optionally using emulsifiers and/ordispersants, whilst if water is used as the diluent, for example,organic solvents may optionally be used as solvating agents ordissolving aids, and transferred into injection vials or ampoules orinfusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

The preparations are administered by the usual methods, preferably byoral or transdermal route, most preferably by oral route. For oraladministration the tablets may, of course contain, apart from theabovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

For parenteral use, solutions of the active substances with suitableliquid carriers may be used.

However, it may sometimes be necessary to depart from the amountsspecified, depending on the body weight, the route of administration,the individual response to the drug, the nature of its formulation andthe time or interval over which the drug is administered. Thus, in somecases it may be sufficient to use less than the minimum dose givenabove, whereas in other cases the upper limit may have to be exceeded.When administering large amounts it may be advisable to divide them upinto a number of smaller doses spread over the day.

The formulation examples which follow illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance according to formula (I) 100 mglactose 140 mg corn starch 240 mg polyvinylpyrrolidone  15 mg magnesiumstearate  5 mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance according to formula (I)  80 mglactose  55 mg corn starch 190 mg microcrystalline cellulose  35 mgpolyvinylpyrrolidone  15 mg sodium-carboxymethyl starch  23 mg magnesiumstearate  2 mg 400 mg

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodiumcarboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C) Ampoule solution active substance according to formula (I) 50 mgsodium chloride 50 mg water for inj.  5 mL

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

1. A compound of formula (I)

wherein, R¹ is —C₁₋₃alkyl or —C₁₋₃haloalkyl; R² is selected from —NHR⁴,—C₁₋₅alkyl, —C₁₋₅haloalkyl, halogen and —S—C₁₋₃alkyl; R³ is a 5-12membered heteroaryl, which group is substituted with —X—R¹⁰ andoptionally further substituted with one or more groups independentlyselected from R⁹; R⁴ is selected from —C₁₋₅alkyl and 5-12 memberedheterocycloalkyl, which heterocycloalkyl can be optionally substitutedwith one or more groups independently selected from R⁵; R⁵ is selectedfrom —C₁₋₅alkyl, —C₁₋₅haloalkyl and —C₁₋₃alkylene-O—C₁₋₃alkyl; R⁹ isselected from —C₁₋₅alkyl, —O—C₁₋₅alkyl, —N(C₁₋₅alkyl)₂, halogen,—C₁₋₃alkylene-O—C₁₋₃alkyl, —C₁₋₅alkylene-N(—C₁₋₅alkyl, —C₁₋₅ alkyl) and5-12 membered heterocycloalkyl, wherein the heterocycloalkyl group canbe optionally substituted with one or more groups independently selectedfrom ═O and —C₁₋₃alkyl, or R⁹ is selected from —C₆₋₁₀aryl and 5-12membered heteroaryl, wherein the aryl and heteroaryl groups can beoptionally and independently substituted with one ore more groupsselected from halogen, —C₁₋₃alkyl, —O—C₁₋₃alkyl, —C₁₋₃haloalkyl,—O—C₁₋₃haloalkyl, —N(C₁₋₅alkyl, C₁₋₅alkyl) and —NH—C₁₋₅alkyl; X is—C₁₋₃alkylene- or —O—; R¹⁰ is-C₆₋₁₀aryl or 5-12 membered heteroaryl,each of which groups can be optionally substituted with one or moregroups selected from halogen, —C₁₋₃alkyl, —O—C₁₋₃alkyl, —C₁₋₃haloalkyland —O—C₁₋₃haloalkyl; or a pharmaceutically acceptable salt thereof. 2.The compound according to claim 1, wherein R¹ is —CH₃.
 3. The compoundaccording to claim 2, wherein R² is —NHR⁴ and R⁴ is a 5-6 memberedheterocycloalkyl, optionally substituted.
 4. The compound according toclaim 3, wherein R⁴ is tetrahydrofuran or piperidine, wherein thepiperidine is substituted with one group selected from —CH₃,—CH₂CH₃,—CH₂CH₂CH₃ and —(CH₂)₂—O—CH₃.
 5. The compound according to claim2, wherein R² is —NHR⁴ and R⁴ is —C₁₋₃alkyl.
 6. The compound accordingto claim 5, wherein R² is —NHR⁴ and R⁴ is —CH₃ or —CH(CH₃)₂.
 7. Thecompound according to claim 2, wherein R² is —C₁₋₃alkyl.
 8. The compoundaccording to claim 7, wherein R³ is a 5-9 membered heteroarylsubstituted with —X—R¹⁰ and optionally further substituted with one ormore groups independently selected from R⁹.
 9. The compound according toclaim 1, wherein —X—R¹⁰ is selected from —CH₂— phenyl, —CH(CH₃)-phenyl,—CH₂-pyridyl, —CH(CH₃)-pyridyl and —O-phenyl, each of which phenyl orpyridyl groups is optionally substituted with —F or —CH₃.
 10. Thecompound according to claim 9, wherein —X—R¹⁰ is selected from —CH₂—phenyl, —CH₂-pyridyl, —CH(CH₃)-phenyl and —CH(CH₃)-pyridyl, each ofwhich pyridyl or phenyl group is optionally substituted with —F or —CH₃.11. The compound according to claim 8, wherein R³ is selected frompyrazolyl, imidazol, benzimidazolyl, imidazopyridine andimidazopyrimidine and R³ is substituted with —X—R¹⁰ and R³ is optionallyfurther substituted with one or more groups independently selected fromR⁹.
 12. The compound according to claim 1, wherein R⁹ is independentlyselected from —C₁₋₃alkyl, —O—C₁₋₃alkyl, —N(C₁₋₃alkyl)₂, phenyl and 6membered heterocycloalkyl, which heterocycloalklyl can be optionallysubstituted with one or more groups independently selected ═O and—C₁₋₃alkyl.
 13. The compound according to claim 11, wherein R³ isimidazopyridine or benzimidazol substituted with —CH₂-phenyl or—CH₂-pyridyl, —CH(CH₃)-pyridyl and optionally further substituted with—C₁₋₃alkyl or 5-12 membered heterocycloalkyl wherein theheterocycloalkyl group can be optionally substituted with one or moregroups independently selected from —C₁₋₃alkyl.
 14. The compoundaccording to claim 13, wherein R³ is imidazopyridine or benzimidazolsubstituted with —CH₂-phenyl, —CH(CH₃)-pyridyl or —CH₂-pyridyl and with—CH(CH₃)₂ or morpholinyl or piperazinyl, wherein the morpholinyl orpiperazinyl groups is optionally substituted with one or more groupsselected from —C₁₋₃alkyl.
 15. A compound selected from Ex# Structure I-1

 I-2

 I-3

 I-4

 I-5

 II-1

 II-2

 II-3

III-1

III-2

III-3

III-4

III-5

III-6

III-7

III-8

III-9

III-10

III-11

III-12

III-13

III-14

III-15

III-16

III-17

III-18

III-19

III-20

III-21

III-22

III-23

III-24

III-25

III-26

III-27

III-28

III-29

III-30

III-31

III-32

III-33

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or a pharmaceutically acceptable salt thereof.
 16. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 1 optionally in combination with one or morepharmaceutically acceptable excipients and/or carriers.
 17. Thepharmaceutical composition according to claim 16 further comprising atleast one other cytostatic or cytotoxic active substance, different fromformula (I).
 18. A method of treating hematopoietic malignanciescomprising administering to a patient a therapeutically effective amountof a compound according to claim
 1. 19. A method of treating AML or MMcomprising administering to a patient a therapeutically effective amountof a compound according to claim
 1. 20. A method of treating lung,liver, colon, brain, thyroid, pancreas, breast, ovary and prostatecancer comprising administering to a patient a therapeutically effectiveamount of a compound according to claim 1.